The limited regenerative capacity of cartilage limits the body's natural capacity to repair damage due to trauma or degenerative disease. For example, osteoarthritis (OA) afflicts up to 70% of individuals over 65 years of age (21 million Americans). Injury to the meniscus or anterior cruciate ligament often leaves the patient at increased risk of arthritis. Osteoarthritis is characterized by a progressive loss of cartilage on the articular surface, leading to a painful exposure of subchondral bone. Following this injury to the articular cartilage, human tissues shows little repair capacity. The nascent cartilage that does appear as a result on an innate repair response is generally fibrous in nature and hence unsuitable for repair.
Various therapeutic regimens have been developed for treating subjects having cartilage damage. Examples of these treatments include those that are intended to trigger cartilage production in the subject using mechanical means (e.g., abrasion and microfracture surgery, such as drilling, microfracture surgery, chondroplasty, and spongialization; laser-assisted treatments, which combine the removal of diseased cartilage with cartilage reshaping) and therapies that rely on transplantation (or grafting) of tissue to the damaged site (e.g., periosteal grafting, osteochondral grafting (mosaicplasty), and articular cartilage paste grafting). Success rates of these therapies vary and some have potential deleterious side effects, including tissue necrosis, reactive synovitis, chondrolysis, and an acceleration of articular cartilage degeneration.
A cell-based cartilage treatment regimen, known as autologous chondrocyte therapy (ACT), involves the removal of chondrocytes from cartilage, the expansion of the cells in vitro, and the administration of these expanded cells into the patient with or without a supporting matrix (or other proteins or proteoglycans). ACT therapy is complicated by the dedifferentiation of human articular chondrocytes when cultured in vitro as well as the relative difficulty of re-differentiating the cells such that they produce abundant cartilage matrix at the graft site. Further, only a small amount of cartilage can be collected from humans, and thus only a small number of chondrocytes can be used for the initiation of the culture. Thus, there is continued difficulty in applying isolated human chondrocytes to transplantation therapy in practice.
Another therapeutic strategy is the utilization of bone marrow-derived mesenchymal stem cells (hbmMSCs). Clinical studies utilizing a single dose of hbmMSCs, (Chondrogen) show a reduction in pain compared to hyaluronic acid (HA) control. However, Mesenchymal stem cells (MSCs) have two hurdles in regard to their use in regenerating cartilage. First, the use of the cells as an allogeneic graft is problematic due to the limited proliferative capacity of adult MSCs, and even if the cells are capable of a certain amount of expansion, they often relatively quickly lose their capacity to form cartilage. The second hurdle is that MSCs, such as bone marrow-derived MSCs form hypertrophic chondrocytes, characterized by high levels of COL10A1 and IHH expression. The role of these chondrocytes in development are to recruit blood vessels and osteoblasts and then die. Hypertrophic chondrocytes are observed for instance in the growth plate regions of long bones. They are also observed at the site of a bone fracture where they similarly play an important role in bone formation. Therefore, the use of MSCs in the treatment of trauma or degenerative diseases of cartilage, such as osteoarthritis have yielded mixed results. In addition, there are numerous types of cartilage in the body. The elastic cartilage of the ear has differing molecular composition than that of the nose, sternum, trachea, and weight-bearing joints.
Therefore, the field of regenerative medicine, particularly in the field of cartilage regeneration and repair, are in great need of novel cellular formulations to generate commercial quantities of diverse types of permanent, as opposed to hypertrophic, chondrocytes.